What are the risks of using Valproate (anticonvulsant) in pregnancy?

Significant Risk of Congenital Malformations with Valproate Use in Pregnancy

Valproate should be avoided in pregnancy due to its substantial risk of causing severe congenital malformations, neurodevelopmental disorders, and other adverse outcomes that significantly impact morbidity and mortality. 1

Major Congenital Malformation Risks

Valproate exposure during pregnancy is associated with multiple serious birth defects:

• Neural tube defects: 1-2% risk compared to 0.14-0.2% in the general population 1
• Overall malformation rate: 10.7% with valproate monotherapy versus 2.9% with other antiepileptic drugs 1
• 4-fold increase in congenital malformations compared to other antiepileptic drugs 1
• Specific malformations with significantly increased risk 2:
  • Spina bifida (OR 12.7)
  • Atrial septal defect (OR 2.5)
  • Cleft palate (OR 5.2)
  • Hypospadias (OR 4.8)
  • Polydactyly (OR 2.2)
  • Craniosynostosis (OR 6.8)
  • Craniofacial defects
  • Cardiovascular malformations
  • Multiple body system anomalies

Dose-Dependent Risk

The risk of malformations is dose-dependent:

• Doses ≥1000mg/day nearly double the risk compared to lower doses (8.86% vs 4.88%) 3
• Neither controlled-release formulations nor divided daily dosing reduces this risk 3

Neurodevelopmental Effects

Beyond physical malformations, valproate exposure in utero is associated with:

• Lower IQ and developmental delay 1
• Increased risk of autism and attention deficit/hyperactivity disorder 1
• Cognitive, language, and psychomotor delays in early childhood 4

Regulatory Status and Warnings

The FDA and other regulatory bodies have issued strong warnings:

• Valproate is classified as having the highest teratogenic risk among neuropsychiatric medications 4
• Many countries have implemented strict restrictions or bans on valproate use in women of childbearing potential 4, 5
• The FDA medication guide explicitly warns about these risks 1

Management Recommendations

For women requiring treatment for epilepsy or other conditions:

1. Alternative medications should be considered first for women of childbearing potential 6, 1
2. If valproate must be used (when no alternative is effective):
   • Use the lowest effective dose, ideally <1000mg/day 7
   • Prescribe as monotherapy rather than in combination with other antiepileptic drugs 7
   • Provide high-dose folic acid supplementation before and during pregnancy 1
   • Implement close antenatal monitoring with specialized testing for neural tube and other defects 1

Important Caveats

• Do not abruptly discontinue valproate in pregnant women with epilepsy without medical supervision, as this could precipitate status epilepticus with risk of hypoxia and threat to life 1
• Women taking valproate should use effective contraception and receive preconception counseling 1
• Pregnancy registry enrollment is recommended for women who become pregnant while taking valproate 1

Valproate's teratogenic effects are not simply a matter of confounding by indication, as the risks are significantly higher than with other antiepileptic drugs used for the same conditions, show dose-dependence, and demonstrate consistency across multiple studies 4.